Risk factors in thyroid cancer: is the obesity pandemic an important factor?

KEYWORDS:

• Obesity
• thyroid cancer
• histologic aggressive features
• body mass index
• management
• epidemiology

In 2016, the International Agency for Research on Cancer (IARC) supported the evidence that the absence of excess body fat was associated with a reduced risk of several cancers, including thyroid (Figure 1). In this study, the subjects with the highest body mass index (BMI) showed a relative risk of having thyroid cancer of 1.1 (95% CI: 1.0–1.1) [1].

Figure 1. The relative risk (RR) of the highest BMI category evaluated (versus normal BMI) in the obesity-related cancers according to the International Agency for Research on Cancer (IARC) working group [1].

Thyroid cancer, particularly in its differentiated forms (DTC), has been growing worldwide during the last decades [2]. Although several factors that could contribute to this phenomenon cannot be overlooked [3], the routine implementation of the neck ultrasound in clinical practice could be considered a key factor in the increase in early-stage clinically undetectable papillary thyroid cancers (PTCs) [4,5]. Likewise, obesity tripled in men and doubled in women in 200 countries, from 1975 to 2014 [6], and interesting data support the hypothesis that if this trend will continue, by the year 2030, 38% and 20% of the world’s adult population will be overweight or obese, respectively [6]. Obesity is considered to be one of the most common causes of carcinogenesis, along with alcohol and smoking [7,8], and is associated with both increased cancer incidence and progression and could contribute to more than 20% of cancer-related deaths [9].

Several studies investigated the potential association between BMI and DTC, particularly PTC. Conversely, other indicators of adiposity such as weight circumference and weight gain, although more precise in quantifying visceral adiposity, which could play a key role in carcinogenesis, were less frequently reported in the literature in relation to DTC. Also, the relationship between obesity and other rarer thyroid cancers such as anaplastic, follicular, or medullary thyroid cancer has rarely been evaluated.

Therefore, the strengths of evidence regarding obesity and prevalence and aggressiveness of PTC are linked to the evaluation of BMI as a measure of fatness.

The pathogenic link between cancers and obesity has been widely studied in recent years [10]. A key role is played by the peculiar function of adipose tissue, an active endocrine organ, which is able to produce not only hormones but also adipokines and growth factors involved in the deregulation of cell growth and survival and in cancer development [9,11].

However, other factors are implicated in thyroid carcinogenesis and could interact with obesity, such as iodine intake, radiation exposure, and endocrine disruptors.

To date, the influence of obesity on the increasing rate of PTC is well recognized. Indeed, based on several large prospective cohort or case–control studies, a positive association was observed between BMI, and less frequently also other indicators of adiposity, and the risk of having PTC [12–14]. This is supported by a recent study that estimated that one in six PTC (16.6%), in 2015 in adults (≥60 years) in the USA, was exclusively due to overweight and obesity [15].

The same association was also observed in rarer and more aggressive thyroid cancers such as follicular or anaplastic [12,15]. Conversely, to date, no association between obesity and medullary thyroid cancer was observed [12,16].

Regarding diagnosis, the European Society for Endocrinology (ESE) guidelines on endocrine work-up in obesity [17] stated that no sufficient data are available to recommend systematic assessment by neck ultrasound in subjects with obesity. However, in clinical practice, thyroid glands in subjects with obesity are often difficult to be evaluated by palpation. Accordingly, the results of the available studies in favor or against the routine use of neck ultrasound in subjects with obesity are controversial [18–20].

More controversies were reported about the potential association of obesity with aggressive features of thyroid cancer [21]. A study involving more than 400,000 subjects observed that those with BMI ≥30 kg/m² had a risk fivefold greater to have larger PTC (>4 cm) when compared to normal weight [15]. Nevertheless, in this study, an association of larger tumors with disease-specific survival and recurrence was postulated, but not demonstrated. Two recent meta-analysis, partially evaluating the same studies, included 26,196 and 35,237 subjects with PTC [22,23], showed a positive association between higher BMI and minimal extrathyroidal extension (mETE), multifocality, larger tumor size, and lymph node metastases.

However, despite this evidence, several limitations were reported by the authors in considering these results: the lack of adjustment for confounding factors, the absence of information about the aggressive variants of PTC, the retrospective observational nature of the studies, and the different ethnicities of the included subjects. It is worth to note that several other cross-sectional studies failed to confirm the association of higher BMI with aggressiveness of DTC, prevalently PTC [24–26].

Regarding recurrence, recent reports failed to demonstrate the association of a higher BMI with a higher recurrence rate of PTC over time [23,27,28].

Regarding molecular biology, subjects with PTC carrying the BRAF V600E mutation could have potentially higher-risk cancers [29]. In a case–control study, overweight and obesity were associated with a higher prevalence of BRAF-positive PTC if compared to normal-weight patients [30]. Despite this finding, no difference was highlighted in the rate of aggressive histologic features among the groups of patients divided according to BMI.

1. Pearls and pitfalls in interpreting studies

The main strength of the studies evaluating the impact of obesity on DTC incidence and aggressiveness is the large cohort of patients evaluated. However, several important information is lacking in most studies or do not allow for a univocal interpretation of the data. The first and most important pitfall is the method used to evaluate body fatness. Indeed, several indicators are available such as waist circumference, waist-to-hip ratio, visceral and subcutaneous adipose tissue, and BMI. Although BMI was the most frequently used, in some patients it could be inaccurate to distinguish between adipose tissue and lean mass. However, none of these measures of adiposity, when considered alone, can completely define obesity status. Concerning BMI, several studies classified patients according to the WHO reference measures for Asian and some others with the reference measures for Caucasian, with ethnicity being an important factor in interpreting these studies. Not all studies have a BMI measured at the same time for all patients from a physician, some studies have self-reported height and weight and clinical evidence suggesting that women tend to underreport their weight, while both men and women tend to overreport their height [31]. This variability in self-reporting height and weight could lead to a bias in interpreting the results evaluating the potential association between higher BMI and thyroid cancer. Moreover, classifying patients into categories does not allow to evaluate the impact of BMI as a continuous variable in several studies.

Most studies evaluating the potential association between obesity and DTC are retrospective and observational, and natural history of obesity was not assessed, and in some cases, the recognized positive association between obesity and aggressiveness of thyroid cancer was not adjusted for confounding factors associated with worse prognosis (i.e. male sex and older age). Moreover, several key factors in worsening the presentation of DTC were not fully considered (i.e. radiation exposure and family history of DTC). Lastly, most studies lack information about drugs with impact on obesity as far as comorbidities influencing the prognosis (i.e. smoking habits, cholesterol status, and diabetes).

2. Interplay between obesity and thyroid cancer: is a personalized management required?

The question if subjects with obesity should require a personalized management, from systemic screening with neck ultrasound up to aggressive surgery in the case of diagnosed thyroid cancer, remains open for debate. The European Society for Endocrinology (ESE) guidelines on the endocrine work-up in obesity [17] do not recommend a systematic neck ultrasound assessment in subjects with obesity. However, because of difficulties in neck palpation in obese subjects and the positive association between obesity and DTC, performing a neck US should be considered when physical examination is not fully comprehensive.

Regarding the therapeutic management of a newly diagnosed DTC, the available evidence does not suggest treating these patients in a personalized way. The major guidelines on the management of DTC [32,33] do not include obesity as a comorbidity influencing its treatment and management.

Although surgery could be more complex in subjects with obesity, the lack of incontrovertible data about the association between obesity and clinical aggressiveness and recurrence of DTC should lead to a management that must follow international consensus guidelines for these patients without peculiar consideration of obesity.

3. Conclusions

The pathogenic role of obesity in the increase in thyroid cancer incidence is well recognized. Changes in lifestyle leading to a decrease in the prevalence of obesity could lead to a parallel decrease in the prevalence of thyroid cancers influenced by obesity. Systematic screening in searching thyroid cancer in subjects with obesity is not justified according to the clinical evidence. However, in those cases of subjects with obesity, the palpation alone is not sufficient and should be followed by a neck ultrasound.

Data on the association between obesity and aggressiveness of thyroid cancer, as far as recurrence, are contrasting. Therefore, thyroid cancer in subjects with obesity should be treated according to the suggestions of the referral guidelines for all patients affected by thyroid cancer, without a tailored management.

Declaration of interest

The author has served as a consultant for Lilly. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Reviewer disclosures

Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.

Additional information

Funding

This paper was not funded.